RESUMEN
Recently identified novel agents that disrupt tubulin polymerization include synthetic spiroketal pyrans (SPIKET) targeting the spongistatin binding site of b-tubulin. These agents exhibit anticancer activity by disrupting normal mitotic spindle assembly and cell division as well as inducing apoptosis. At nanomolar concentrations, the SPIKET compound SPIKET-P caused tubulin depolymerization in cell-free turbidity assays and exhibited potent cytotoxic activity against cancer cells as evidenced by destruction of microtubule organization, and prevention of mitotic spindle formation in human breast cancer cells. SPIKET compounds represent a new class of tubulin targeting agents that show promise as anti-cancer drugs.
Asunto(s)
Antineoplásicos/farmacología , Piranos/farmacología , Compuestos de Espiro/farmacología , Tubulina (Proteína)/efectos de los fármacos , Animales , Sitios de Unión , Humanos , Piranos/metabolismo , Compuestos de Espiro/metabolismo , Tubulina (Proteína)/metabolismoRESUMEN
A novel mono-THF containing synthetic anticancer drug, COBRA-1, was designed for targeting a previously unrecognized unique narrow binding cavity on the surface of alpha-tubulin. COBRA-1 inhibited GTP-induced tubulin polymerization in cell-free tubulin turbidity assays. Treatment of human breast cancer and brain tumor (glioblastoma) cells with COBRA-1 caused destruction of microtubule organization and apoptosis. Like other microtubule-interfering agents, COBRA-1 activated the proapoptotic c-Jun N-terminal kinase (JNK) signal transduction pathway, as evidenced by rapid induction of c-jun expression.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Furanos/química , Furanos/farmacología , Tubulina (Proteína)/efectos de los fármacos , Diseño de Fármacos , Humanos , Modelos Moleculares , Tubulina (Proteína)/metabolismo , Células Tumorales CultivadasRESUMEN
A novel mono-THF containing synthetic anticancer drug (WHI-261) was designed for targeting a previously unrecognized unique narrow binding cavity on the surface of tubulin. The anti-cancer activity of WHI-261 was confirmed using MTT assays. The structure-based design, synthesis, and biological activity of WHI-261 are reported.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Alcoholes Grasos/química , Alcoholes Grasos/farmacología , Furanos/química , Furanos/farmacología , Tubulina (Proteína)/metabolismo , Antineoplásicos/metabolismo , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Alcoholes Grasos/metabolismo , Furanos/metabolismo , Humanos , Modelos Moleculares , Conformación Proteica , Tubulina (Proteína)/química , Células Tumorales CultivadasRESUMEN
SPIKET-P, a novel synthetic spiroketal pyran, was rationally designed as a pharmocophore for the tubulin depolymerizing marine natural product Spongistatin 1. SPIKET-P was prepared from the commercially available benzyl (R)-(-)-glycidyl ether using a versatile 11-step synthetic scheme in a stereocontrolled fashion. At nanomolar concentrations, SPIKET-P caused tubulin depolymerization in cell-free turbidity assays and exhibited potent cytotoxic activity against cancer cells as evidenced by destruction of microtubule organization, and prevention of mitotic spindle formation in human breast cancer cells.
Asunto(s)
Antineoplásicos/síntesis química , Éteres Cíclicos/química , Lactonas/química , Macrólidos , Piranos/síntesis química , Compuestos de Espiro/síntesis química , Tubulina (Proteína)/efectos de los fármacos , Animales , Antineoplásicos/farmacología , Neoplasias de la Mama/patología , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Mitosis/efectos de los fármacos , Modelos Moleculares , Nefelometría y Turbidimetría , Poríferos/química , Piranos/farmacología , Compuestos de Espiro/farmacología , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Agents that either promote or inhibit tubulin polymerization exhibit anticancer activity by disrupting normal mitotic spindle assembly and cell division as well as inducing apoptosis. Recently identified novel agents that target tubulin include synthetic spiroketal pyrans (SPIKET), targeting the spongistatin binding site of beta-tubulin, and COBRA compounds, targeting a unique binding cavity on alpha-tubulin. At nanomolar concentrations, the SPIKET compound SPIKET-P caused tubulin depolymerization in cell-free turbidity assays and exhibited potent cytotoxic activity against cancer cells as evidenced by destruction of microtubule organization, and prevention of mitotic spindle formation in human breast cancer cells. Molecular modeling studies predicted a high-affinity interaction of the first COBRA compounds, COBRA-0 and COBRA-1, with a unique hydrophobic binding site on alpha-tubulin located between the GTP/GDP binding site and the M-loop. Further studies showed that COBRA-1 inhibited GTP-induced tubulin polymerization in cell-free tubulin turbidity assays. Treatment of human breast cancer and brain tumor (glioblastoma) cells with COBRA-1 caused destruction of microtubule organization and apoptosis. COBRA-1 activated the pro-apoptotic c-Jun N-terminal kinase (JNK) signal transduction pathway. COBRA and SPIKET compounds represent two new classes of tubulin targeting agents that show promise as anticancer drugs.
Asunto(s)
Antineoplásicos/farmacología , Furanos/farmacología , Piranos/farmacología , Compuestos de Espiro/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Furanos/síntesis química , Furanos/uso terapéutico , Humanos , Neoplasias/tratamiento farmacológico , Piranos/síntesis química , Piranos/uso terapéutico , Compuestos de Espiro/síntesis química , Compuestos de Espiro/uso terapéuticoRESUMEN
We synthesized a novel compound, 5-bromo-6-methoxy-5,6-dihydro-AZT-5'- (p-bromophenyl methoxyalaninyl phosphate), which had an EC50 value of 5 microM in sperm motility assays. This is > 1 log10 better than that of the detergent spermicide nonoxynol-9 (EC50 81 microM). The compound also displayed a potent anti-human immunodeficiency virus (HIV) activity with an IC50 value of 0.005 microM in HIV replication assays, which was virtually identical to that of AZT (IC50 0.006 microM) and > 2 log10 more potent than that of nonoxynol-9 (IC50 2.2 microM). The promising results reported herein recommend the further development of the dual function 5-halo-6-alkoxyl-5,6-dihydro-AZT derivatives as a new class of vaginal contraceptives capable of preventing the sexual transmission of HIV while providing fertility control for women who are at high risk of acquiring HIV by heterosexual transmission. These dual function 5-halo-6-alkoxyl-5,6-dihydro-AZT derivatives may also have utility in curbing domestic and wildlife animal retroviral transmissions.
Asunto(s)
Compuestos Organofosforados/síntesis química , Zidovudina/análogos & derivados , Zidovudina/síntesis química , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Dispositivos Anticonceptivos Femeninos , Didesoxinucleótidos , Femenino , VIH/efectos de los fármacos , Infecciones por VIH/prevención & control , Humanos , Masculino , Nonoxinol/farmacología , Compuestos Organofosforados/farmacología , Espermicidas/síntesis química , Espermicidas/farmacología , Espermatozoides/efectos de los fármacos , Replicación Viral/efectos de los fármacos , Zidovudina/farmacologíaRESUMEN
The potency and selectivity index of the AZT-phenyl phosphate derivatives in thymidine kinase (TK)-deficient T cells were substantially enhanced by introducing a single para-bromo substitutent in the phenyl moiety. AZT-5'-(p-bromophenyl methoxyalaninyl phosphate) was 43-fold more potent than AZT-5'-(phenyl methoxyalaninyl phosphate) and was fivefold more potent than AZT in inhibiting human immunodeficiency virus (HIV) replication in TK-deficient CEM cells.
Asunto(s)
Fármacos Anti-VIH/farmacología , Compuestos Organofosforados/uso terapéutico , Zidovudina/análogos & derivados , Zidovudina/farmacología , Fármacos Anti-VIH/síntesis química , Didesoxinucleótidos , Transcriptasa Inversa del VIH/antagonistas & inhibidores , VIH-1/efectos de los fármacos , VIH-1/enzimología , VIH-1/genética , Humanos , Compuestos Organofosforados/farmacología , Nucleótidos de Timina , Replicación Viral/efectos de los fármacos , Replicación Viral/genética , Zidovudina/síntesis química , Zidovudina/uso terapéuticoRESUMEN
Diethylstilbestrol (DES) and hexestrol (HES) are carcinogenic synthetic estrogens. The major metabolites of these compounds are their catechol derivatives, 3'-OH-DES and 3'-OH-HES. Oxidation of these metabolites leads to the electrophilic quinones, which are presumably involved in the tumor-initiating process. A synthetic route based on the McMurry coupling reaction was developed for the synthesis of 3'-OH-DES. Using commercially inexpensive starting materials, this compound was synthesized in four steps, and the cis and trans isomers were separated and identified. Following the same synthetic route, 3'-OH-HES was synthesized in five steps.
Asunto(s)
Catecoles/síntesis química , Dietilestilbestrol/síntesis química , Congéneres del Estradiol/síntesis química , Hexestrol/síntesis química , Catecoles/química , Catecoles/metabolismo , Cromatografía Líquida de Alta Presión , Dietilestilbestrol/química , Dietilestilbestrol/metabolismo , Congéneres del Estradiol/química , Congéneres del Estradiol/metabolismo , Hexestrol/química , Hexestrol/metabolismo , Espectroscopía de Resonancia Magnética , Espectrometría de MasasRESUMEN
Hexestrol (HES), a synthetic nonsteroidal estrogen, is carcinogenic in Syrian golden hamsters. The major metabolite of HES is its catechol, 3'-OH-HES, which can be metabolically converted to the electrophilic catechol quinone, HES-3',4'-Q, by peroxidases and cytochrome P450. Standard adducts were synthesized by reacting HES-3',4'-Q with dG and dA to produce the adducts 3'-OH-HES-6'(alpha, beta)-N7Gua and HES-3',4'-Q-6'-N6dA, respectively. When HES-3',4'-Q was reacted with calf thymus DNA, 3'-OH-HES-6'(alpha,beta)-N7Gua was identified by HPLC and tandem mass spectrometry as the depurinating adduct, with minor amounts of stable adducts. 3'-OH-HES was bound to DNA after activation by horseradish peroxidase, lactoperoxidase, or rat liver microsomes. The depurinating adduct 3'-OH-HES-6'(alpha, beta)-N7Gua was identified in these systems at levels of 65, 41, and 11 micromol/mol of DNA-P, respectively. Unidentified stable adducts were observed in much lower amounts and were quantified by the 32P-postlabeling method. Similarly to 3'-OH-HES, the catechol metabolites of the natural steroidal estrogens estrone (E1) and estradiol (E2), namely, 2-OHE1, 4-OHE1, 2-OHE2, and 4-OHE2, can be oxidized to their corresponding quinones by peroxidases and cytochrome P450. The quinones of the carcinogenic 4-OHE1 and 4-OHE2 have chemical and biochemical properties similar to those of HES-3',4'-Q. The results suggest that formation of HES-3',4'-Q may be a critical event in tumor initiation by HES and that HES is an excellent model compound to corroborate the hypothesis that estrogen-3,4-quinones are ultimate carcinogenic metabolites of the natural steroidal estrogens E1 and E2.
Asunto(s)
Carcinógenos/metabolismo , Aductos de ADN/metabolismo , Estrógenos no Esteroides/metabolismo , Hexestrol/metabolismo , Animales , Biotransformación , Carcinógenos/toxicidad , Cromatografía Líquida de Alta Presión , Cricetinae , Estrógenos no Esteroides/toxicidad , Hexestrol/toxicidad , Técnicas In Vitro , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Quinonas/química , Quinonas/metabolismo , Ratas , Espectrometría de Masa Bombardeada por Átomos VelocesRESUMEN
Aryl phosphate derivatives of 3'-deoxythymidine (3dT), albeit more active than 3dT in thymidine kinase (TK)-deficient cells, are not potent anti-human immunodeficiency virus (HIV) agents and are capable of inhibiting HIV replication only at micromolar concentrations.
Asunto(s)
Fármacos Anti-VIH/química , Fosfatos/química , Timidina/análogos & derivados , Fármacos Anti-VIH/farmacología , Antivirales/química , Antivirales/farmacología , Humanos , Espectroscopía de Resonancia Magnética , Estructura Molecular , Fosfatos/farmacología , Replicación Viral/efectos de los fármacosRESUMEN
d4T-5'-[p-Bromophenyl methoxyalaninyl phosphate] (d4T-pBPMAP), a novel phenyl phosphate derivative of 2',3'-didehydro-2',3'-dideoxythymidine (d4T) that has an enhanced ability to undergo hydrolysis due to the electron withdrawing properties of its single bromo substituent at the para-position of the phenyl moiety, was found to yield substantially more of the key metabolite alaninyl d4T monophosphate (A-d4T-MP) than the unsubstituted d4T-5'-phenyl methoxyalaninyl phosphate or para-methoxy substituted d4T-5'-phenyl methoxyalaninyl phosphate. d4T-pBPMAP was tested for its anti-HIV-1 activity in peripheral blood mononuclear cells (PBMNC) and thymidine kinase (TK)-deficient CEM T-cells. d4T-pBPMAP was 12.6-fold more potent than the parent compound d4T in inhibiting p24 production (IC50 values: 44 nM vs 556 nM) and 41.3-fold more potent than d4T in inhibiting the reverse transcriptase (RT) activity (IC50 values: 57 nM vs 2355 nM) in HIV-1-infected TK-deficient CEM cells. Similarly, d4T-pBPMAP was more potent than the unsubstituted or para-methoxy substituted phenyl methoxyalaninyl phosphate derivatives of d4T. d4T-pBPMAP did not exhibit any detectable cytotoxicity to PBMNC or CEM cells at concentrations as high as 10,000 nM. Notably, d4T-pBPMAP was capable of inhibiting the replication of a zidovudine (ZDV/AZT)-resistant HIV-1 strain as well as HIV-2 in PBMNC at nanomolar concentrations. To our knowledge, this is the first demonstration that the potency of the d4T-aryl-phosphate derivatives can be substantially enhanced by introducing a single para-bromo substituent in the aryl moiety.